Metalloproteinases (MMPs) are a naturally occurring superfamily of proteinases (enzymes) found in most mammals. The superfamily is composed of at least 26 members of zinc-containing enzymes produced by many cell types and sharing structural and functional features. Based on structural and functional considerations proteinases have been classified into different families and subfamilies (Vartak et al., (2007), J. Drug Targeting, 15, 1-20; and Hopper, (1994), FEBS, 354, 1-6), such as collagenases (MMP-1, -8 and -13), gelatinases (MMP-2, and -9), metalloelastases (MMP-12), the MT-MMPs (MMP-14, -15, -16, -17, -24 and 25), matrilysins (MMP-7 and -26), stromelysins (MMP-3, -10 and -11) and sheddases such as TNF-converting enzymes (TACE, and ACE).
Metalloproteinases are believed to be important in physiological disease processes that involve remodeling such as embryonic development, bone formation and uterine remodeling during menstruation. One major biological function of MMPs is to catalyze the breakdown of connective tissues or extra-cellular matrix by their ability to hydrolyze various components of tissue or matrix. Apart from their role in degrading connective tissue, MMPs are involved in the activation of zymogen (pro) forms of other MMPs thereby inducing MMP activation. They are also involved in the biosynthesis of TNF-alpha which is implicated in many pathological conditions.
MMP-12, also known as macrophage elastase or metalloelastase, is expressed in activated macrophages and has been shown to be secreted from alveolar macrophages from smokers as well as in foam cells in atherosclerotic lesions. MMP-12 knockout mouse studies have shown the development of significant emphysema, thus supporting its role in COPD. MMP-9 (gelatinase B, 92 kDa type IV collagenase) is one member of the MMP family that is released as a proenzyme and subsequently activated via a protease cascade in vivo.
The concentration of MMP-9 is increased in diseases like asthma, interstitial pulmonary fibrosis (IPF), adult respiratory distress syndrome (ARDS), and in chronic obstructive pulmonary disease (COPD). Because of its proteolytic ability, MMP-9 has been implicated in tissue remodelling of the airways and lungs in chronic inflammatory diseases such as severe asthma and COPD. MMP-9 is also likely to be physiologically important because of its ability to regulate the digestion of components of the extracellular matrix as well as the activity of other proteases and cytokines. MMP-9 is secreted in neutrophils, macrophages, osteoclasts, which are easily induced by cytokines and growth factors, and plays a role in various physiological and pathological processes.
Over-expression or over-activation of an MMP, or an imbalance between an MMP and a natural (i.e., endogenous) tissue inhibitor of a matrix metalloproteinase (TIMP) has been linked to a pathogenesis of diseases characterized by the breakdown of connective tissue or extracellular matrix.
Inhibition of the activity of one or more MMPs may be of benefit in treatment of various inflammatory, autoimmue and allergic diseases such as, inflammation of the joint, inflammation of the GI tract, inflammation of the skin, collagen remodeling, wound healing disorders etc.
The design and therapeutic application of MMP inhibitors has revealed that the requirement of a molecule to be an effective inhibitor of MMP class of enzymes is a functional group (e.g. carboxylic acid, hydroxamic acid or sulphydryl) capable of chelating to the active site Zn ion (Whittaker et al., Chem. Rev., (1999), 99; 2735-76).
WO 2004/110974 discloses compounds and their physiologically functional derivatives described as inhibitors of matrix metalloproteinase enzymes. WO 2004/113279 discloses alleged inhibitors of matrix metalloproteinase. WO 2005/026120 discloses compounds also described as inhibitors of matrix metalloproteinase. U.S. Pat. No. 6,350,885 discloses tricyclic heteroaromatic compounds and their derivatives believed to be inhibitors of matrix metalloproteinases. WO 98/09940 discloses biphenyl butyric acids and their derivatives described as inhibitors of matrix metalloproteinases. J. Med. Chem., (1968), vol. 11(6), 1139-1144 discloses the synthesis and anti-inflammatory activity of 4-(p-biphenylyl)-3-hydroxybutyric acid and related compounds. WO 96/15096 discloses substituted 4-biarylbutyric or 5-biarylpentanoic acids and derivatives as alleged matrix metalloproteinase inhibitors. WO 2006/090235 describes 5-phenyl-pentanoic acid derivatives described as matrix metalloproteinase inhibitors for the treatment of asthma and other diseases.
Research has been carried out into the identification of inhibitors that are selective, e.g., for a few of the MMP subtypes. An MMP inhibitor of improved selectivity would avoid potential side effects associated with inhibition of MMPs that are not involved in the pathogenesis of the disease being treated.
Further, use of more selective MMP inhibitors would require administration of a lower amount of the inhibitor for treatment of disease than would otherwise be required and, after administration, partitioned in vivo among multiple MMPs. Still further, the administration of a lower amount of compound would improve the margin of safety between the dose of the inhibitor required for therapeutic activity and the dose of the inhibitor at which toxicity is observed.
Many drugs exist as asymmetric three-dimensional molecules i.e., chiral and will therefore have several stereoisomers depending upon the number of chiral centers present. The importance of evaluating new chemical entities having chiral centers as single isomers is to understand their effect on pharmacological and toxicological aspects. There are often pharmacodynamic, pharmacokinetic and/or toxicological differences between enantiomers/diastereomers. Even if natural physiological mediators are achiral, based on their target environment, their receptors/enzymes may demonstrate a preference for only one optically pure enantiomer of agonists, antagonists or inhibitors. From a pharmacokinetics point of view, chirality can have an influence on drug absorption, distribution, metabolism and elimination. Pure single isomers may also offer advantages in terms of these pharmacokinetic parameters thus enabling better developability of such molecules as drug candidates. It is also known that chirality has a significant effect of the physicochemical properties and crystallinity of a chiral molecule which in turn have profound effects on the pharmacokinetics and developability of the molecule. Besides those mentioned above, regulatory principles guide one to preferably develop single isomers as drug candidates in order to avoid any pharmacological, pharmacokinetic and toxicological problems that may arise due to interactions of an unwanted isomer with undesirable molecular targets.
In this context, synthetic strategies to produce pure single isomers offer advantages over analytical techniques of separation of isomer not only in terms of cost and efficiency but larger amounts of compound can be prepared for elaborate pharmaceutical testing. Thus, compounds of present invention, which are single chiral isomers, have improved potency, improved pharmacokinetics and/or improved physicochemical properties as compared to racemic compounds.
The present invention is directed to overcoming problems encountered in the art.